Polymeric emulsion delivery systems

ABSTRACT

Provided herein are compositions comprising an oil-in-water emulsion, wherein the emulsion comprises a liquid oil component; a cross-linked homopolymer based on acrylic acid and/or a cross-linked copolymer of acrylic acid and acrylic acid esters; and water. In some embodiments, the composition is a vehicle for the delivery of an active agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/377,126, filed Apr. 5, 2019, which claims priority to U.S.Provisional Patent Application No. 62/653,369, filed Apr. 5, 2018, theentire contents of which are incorporated by reference herein for allpurposes.

BACKGROUND OF THE INVENTION

Topical administration is a preferred route of administration for localdelivery of many active agents. A key aspect of topical administrationis designing a delivery system that delivers an optimal concentration ofactive agent at the site of action for an appropriate duration of time.

There remains a need for compositions and vehicles for delivering anactive agent.

BRIEF SUMMARY OF THE INVENTION

In one aspect, topical pharmaceutical compositions are provided. In someembodiments, the topical composition comprises:

-   -   a liquid oil component;    -   a cross-linked homopolymer based on acrylic acid as a first        emulsifier; and    -   water;    -   wherein the composition forms a stable oil-in-water emulsion.

In some embodiments, the liquid oil component is present in an amount ofabout 30% or less by weight of the composition. In some embodiments, theliquid oil component is present in an amount of about 20% or less byweight of the composition. In some embodiments, the liquid oil componentcomprises mineral oil, light mineral oil, a fatty alcohol, amonocarboxylic acid ester, a dicarboxylic acid ester, a medium chaintriglyceride, a long chain triglyceride, or a combination thereof.

In some embodiments, the cross-linked homopolymer is present in anamount of about 0.01-5% by weight of the composition. In someembodiments, the cross-linked homopolymer is present in an amount ofabout 0.01-3% by weight of the composition. In some embodiments, thecross-linked homopolymer is a carbomer homopolymer type A and/orcarbomer homopolymer type C.

In some embodiments, the liquid oil component and the cross-linkedhomopolymer are present in a ratio in the range of about 1:1 to about28:1. In some embodiments, the liquid oil component and the cross-linkedhomopolymer are present in a ratio in the range of about 1:1 to about20:1. In some embodiments, the liquid oil component and the cross-linkedhomopolymer are present in a ratio in the range of about 3:1 to about10:1.

In some embodiments, the composition further comprises a surfactant or across-linked copolymer of acrylic acid and acrylic acid esters as asecond emulsifier. In some embodiments, the composition comprises across-linked copolymer of acrylic acid and acrylic acid esters in anamount of about 0.01-3% by weight of the composition. In someembodiments, the cross-linked copolymer of acrylic acid and acrylic acidesters is a carbomer copolymer type B and/or a carbomer copolymer typeA. In some embodiments, the composition comprises a nonionic, anionic,or cationic surfactant in an amount up to about 0.5% by weight of thecomposition. In some embodiments, the composition comprises a nonionicsurfactant selected from the group consisting of sorbitan esters,polyoxyethylene derivatives of a sorbitan ester, glyceryl monostearate,polyoxyethylene monooleate, polyoxyethylene monostearate andpolyoxyethylene monolaurate. In some embodiments, the compositioncomprises an anionic surfactant selected from the group consisting of analkali soap, an amine soap, and a detergent. In some embodiments, thecomposition comprises a cationic surfactant selected from the groupconsisting of quaternium ammonium salts and quaternary amine salts. Insome embodiments, the composition does not comprise a second emulsifier.

In some embodiments, the composition further comprises an active agent.

In some embodiments, the oil-in-water emulsion is stable for at least 24hours at 40° C. In some embodiments, the oil-in-water emulsion is stablefor at least 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or longer at roomtemperature (22-25° C.). In some embodiments, the oil-in-water emulsionis stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months orlonger at room temperature. In some embodiments, the oil-in-wateremulsion is stable for at least 1, 2, 3, 4, or 5 years or longer at roomtemperature.

In another aspect, a topical pharmaceutical composition comprises:

-   -   a liquid oil component, wherein the liquid oil component is in        an amount of about 30% or less by weight of the composition;    -   a polymer selected from the group consisting of a cross-linked        homopolymer based on acrylic acid in an amount of about 0.01-5%        by weight of the composition, a cross-linked copolymer of        acrylic acid and acrylic acid esters in an amount of about        0.01-5% by weight of the composition, and combinations thereof;        and    -   water.

In some embodiments, the composition comprises a polymer that is across-linked homopolymer based on acrylic acid. In some embodiments, thecomposition comprises a cross-linked homopolymer based on acrylic acidin an amount of about 0.01-3% by weight of the composition. In someembodiments, the cross-linked homopolymer based on acrylic acid is acarbomer homopolymer type A, a carbomer homopolymer type B, or acarbomer homopolymer type C. In some embodiments, the carbomerhomopolymer is a carbomer homopolymer type A.

In some embodiments, the composition comprises a polymer that is across-linked copolymer of acrylic acid and acrylic acid esters. In someembodiments, the composition comprises a cross-linked copolymer ofacrylic acid and acrylic acid esters in an amount of about 0.01-3% byweight of the composition. In some embodiments, the cross-linkedcopolymer of acrylic acid and acrylic acid esters is a carbomercopolymer type B and/or a carbomer copolymer type A.

In some embodiments, the polymer is a combination of a cross-linkedhomopolymer based on acrylic acid and a cross-linked copolymer ofacrylic acid and acrylic acid esters. In some embodiments, the polymeris a combination of a carbomer homopolymer type A and a carbomercopolymer type B. In some embodiments, the ratio of the amount of thecross-linked homopolymer based on acrylic acid to that of thecross-linked copolymer of acrylic acid and acrylic acid esters is in therange of 1.6:1 to about 100:1.

In some embodiments, the liquid oil component is present in an amount ofabout 20% or less by weight of the composition. In some embodiments, theliquid oil component and the polymer are present in a ratio in the rangeof about 1:1 to about 28:1. In some embodiments, the liquid oilcomponent and the polymer are present in a ratio in the range of about1:1 to about 20:1. In some embodiments, the liquid oil component and thepolymer are present in a ratio in the range of about 3:1 to about 10:1.In some embodiments, the liquid oil component comprises mineral oil,light mineral oil, a fatty alcohol, a monocarboxylic acid ester, adicarboxylic acid ester, a medium chain triglyceride, a long chaintriglyceride, or a combination thereof.

In some embodiments, the composition further comprises an active agent.

In another aspect, kits are provided. In some embodiments, the kitcomprises a topical pharmaceutical composition as disclosed herein. Insome embodiments, the kit further comprises instructions for use, e.g.,according to a method as disclosed herein. In some embodiments, the kitis for use in treating a condition or disorder as disclosed herein,e.g., a skin condition or disorder.

In still another aspect, therapeutic methods comprising the use of atopical pharmaceutical composition as disclosed herein are provided. Insome embodiments, the method comprises administering a topicalpharmaceutical composition as disclosed herein to a subject in needthereof.

DETAILED DESCRIPTION OF THE INVENTION I. Introduction

Disclosed herein are pharmaceutical compositions (such as topicalcompositions) comprising an oil-in-water emulsion, wherein the emulsioncomprises a liquid oil component; one or both of a cross-linkedhomopolymer based on acrylic acid and a cross-linked copolymer ofacrylic acid and acrylic acid esters; and water. In some embodiments,the composition is a vehicle for the delivery of an active agent. Asdetailed herein, it has been discovered that cross-linked polymers basedon acrylic acid form emulsions that provide stable conditions whereemulsion droplets retain their distribution across time and temperature,active pharmaceutical ingredients retain their chemical integrity evenwithout the presence of stabilizing agents, such as sequestering oranti-oxidant agents, and dermal and ocular disposition of a given activepharmaceutical ingredient can be enhanced.

Furthermore, as detailed herein, it has been surprisingly discoveredthat cross-linked homopolymers based on acrylic acid can function as afirst emulsifier to form a stable emulsion with an oil component, evenin the absence of a surfactant or another polymeric component (i.e.,without a second emulsifier). Thus, in another aspect, the presentdisclosure relates to compositions comprising a liquid oil component, across-linked homopolymer based on acrylic acid as a first emulsifier,and water, wherein the amount of the cross-linked homopolymer based onacrylic acid is sufficient to form a stable oil-in-water emulsion in theabsence of a surfactant or another polymeric component (e.g.,cross-linked copolymer of acrylic acid and acrylic acid esters).

II. Definitions

As used herein, the singular forms “a”, “an” and “the” include pluralreferents unless the content clearly dictates otherwise. The terms“about” and “approximately,” when used to modify an amount specified ina numeric value or range, indicate that the numeric value as well asreasonable deviations from the value known to the skilled person in theart, for example, ±20%, ±10%, or +5%, or ±2.5%, or 1%, or ±0.5%, arewithin the intended meaning of the recited value.

As used herein, the term “cross-linked homopolymer based on acrylicacid” refers to a polymer comprising acrylic acid polymer chains thatare cross-linked to each other. In some embodiments, the homopolymer isa predominantly high molecular weight cross-linked homopolymer ofacrylic acid as described herein.

As used herein, the term “cross-linked copolymer of acrylic acid andacrylic acid esters” refers to a polymer comprising acrylic acid andacrylic acid ester copolymers (e.g., block copolymers) that arecross-linked to each other. In some embodiments, the copolymer is apredominantly high molecular weight cross-linked copolymer of acrylicacid and alkyl acrylate.

As used herein, the term “active agent” refers to a chemical material orcompound that induces a desired pharmacological or physiological effect,and include agents that are therapeutically effective, prophylacticallyeffective, or cosmeceutically effective. The term also encompassespharmaceutically acceptable, pharmacologically active derivatives andanalogs of those active agents specifically mentioned herein, including,but not limited to, salts, esters, amides, prodrugs, active metabolites,inclusion complexes, analogs, and the like.

As used herein, the term “therapeutically effective amount” refers to anamount of an agent (e.g., an active agent) that treats, alleviates,abates, or reduces the severity of symptoms of disease in a subject. Insome embodiments, a therapeutically effective amount of an agent (e.g.,an active agent) diminishes symptoms, makes an injury, disease, orcondition (e.g., a skin disorder) more tolerable, slows the rate ofdegeneration or decline, or improves a patient's physical or mentalwell-being. The effect of treatment can be compared to an individual orpool of individuals not receiving the treatment, or to the same patientprior to treatment or at a different time during treatment.

The term “administer” refers to a method of delivering agents,compounds, or compositions to the desired site of biological action.These methods include, but are not limited to, topical delivery orocular delivery. In some embodiments, a composition as disclosed hereinis administered topically (e.g., by applying a thin film of a lotionformulation to the affected area, such as the face, back, neck orshoulders of a subject with acne).

The terms “subject,” “individual,” and “patient,” as usedinterchangeably herein, refer to a mammal, including but not limited tohumans, non-human primates, rodents (e.g., rats, mice, and guinea pigs),rabbits, dogs, cows, pigs, horses, and other mammalian species. In someembodiment, a subject, individual, or patient is a human.

III. Compostions

In one aspect, the present disclosure provides compositions such astopical compositions comprising a liquid oil component and one or bothof a cross-linked homopolymer based on acrylic acid and a cross-linkedcopolymer of acrylic acid and acrylic acid esters, wherein thecomposition is an oil-in-water emulsion. In some embodiments, thecomposition is a vehicle for the delivery of an active agent. In someembodiments, the composition is formulated as a lotion (e.g., anoil-in-water emulsion or a water-in-oil emulsion). In some embodiments,the composition is formulated as a cream.

Compositions Comprising Polymeric Emulsifiers

Compositions according to the present disclosure generally include across-linked homopolymer as the first emulsifier. The first emulsifiercan be considered a “primary emulsifier,” as it is generally sufficientto form a stable emulsion with an oil component. In some embodiments,the first emulsifier is used in the absence of another emulsifier. Insome embodiments, the first emulsifier is used in the presence of one ormore other emulsifiers, i.e., in addition to the first emulsifier, thecomposition contains a second emulsifier, such as a surfactant and/oranother polymeric component (e.g., a cross-linked copolymer of acrylicacid and acrylic acid esters).

In some embodiments, a composition (such as a topical composition)comprises:

-   -   a liquid oil component;    -   a cross-linked homopolymer based on acrylic acid as a first        emulsifier; and    -   water;    -   wherein the composition forms a stable oil-in-water emulsion.

In some embodiments, a composition (such as a topical composition)comprises an oil-in-water emulsion, wherein the emulsion comprises:

-   -   a liquid oil component;    -   a cross-linked homopolymer based on acrylic acid as a first        emulsifier; and    -   water;    -   wherein the amount of the cross-linked homopolymer is sufficient        to form a stable oil-in-water emulsion in the absence of a        surfactant or a cross-linked copolymer of acrylic acid and        acrylic acid esters.

In some embodiments, the cross-linked homopolymer is present in anamount of about 0.01-5% by weight of the composition. In someembodiments, the cross-linked homopolymer is present in an amount ofabout 0.01-4% by weight of the composition, or in an amount from about0.01-3% by weight of the composition, or in an amount from about 0.01-2%by weight of the composition, or in an amount from about 0.01-1% byweight of the composition, or in an amount from about 0.05-5% by weightof the composition, or in an amount from about 0.05-2.5% by weight ofthe composition, or in an amount from about 0.05-1.5% by weight of thecomposition, or in an amount from about 0.05-1% by weight of thecomposition. In some embodiments, the cross-linked homopolymer ispresent in an amount of about 0.01%, or about 0.05%, or about 0.1%, orabout 0.2%, or about 0.3%, or about 0.4%, or about 0.5%, or about 0.6%,or about 0.7%, or about 0.8%, or about 0.9%, or about 1%, or about 1.5%,or about 2%, or about 2.5%, or about 3%, or about 3.5%, or about 4%, orabout 4.5%, or about 5% by weight of the composition.

In some embodiments, the liquid oil component is present in an amount ofabout 30%, or less (such as 0.01-30%, 0.1-30%, or 0.1-25%), by weight ofthe composition. In some embodiments, the liquid oil component ispresent in an amount of about 20%, or less (such as 0.01-20% or0.5-20%), by weight of the composition. In some embodiments, the liquidoil component is present in an amount of about 15% or less by weight ofthe composition, or about 10% or less by weight of the composition, orabout 8% or less by weight of the composition. In some embodiments, theliquid oil component is present in an amount of about 1-20% by weight ofthe composition, or in an amount from about 1% to about 15% by weight ofthe composition, or in an amount from about 1% to about 10% by weight ofthe composition, or in an amount from about 1% to about 5% by weight ofthe composition, or in an amount from about 2% to about 4% by weight ofthe composition. In some embodiments, the liquid oil component ispresent in an amount of about 5-20% by weight of the composition, or inan amount of about 5-15% by weight of the composition, or in an amountof about 5-10% by weight of the composition. In some embodiments, theliquid oil component is present in an amount up to about 10% by weightof the composition, e.g., up to about 8%, up to about 7.5%, up to about7%, up to about 6%, up to about 5%, up to about 4.5%, up to about 4%, upto about 3.5%, up to about 3%, or up to about 2.5%.

In some embodiments, the oil component is present in an amount up toabout 5% by weight of the composition, e.g., up to about 4.5%, up toabout 4%, up to about 3.5%, up to about 3%, or up to about 2.5%. Theamount of the oil component can range from about 1.5% to about 2.5%, orfrom about 1% to about 3%, or from about 0.5% to about 3.5%, or fromabout 0.25% to about 4%, or from about 0.1% to about 5%, or from about0.05% to about 5.5% by weight of the composition. In some embodiments,the oil component is present in an amount ranging from about 2% to about4% by weight of the composition, e.g., about 2%, about 2.5%, about 3%,about 3.5%, or about 4% by weight of the composition. In someembodiments, the oil component is present in an amount ranging fromabout 1% to about 5% by weight of the composition. In some embodiments,the oil component is present in an amount ranging from about 1.5% toabout 4% by weight of the composition. In some embodiments, the oilcomponent is present in an amount ranging from about 2% to about 4% byweight of the composition. In some embodiments, the oil component ispresent in an amount ranging from about 1% to about 3% by weight of thecomposition.

In some embodiments, the ratio of the amount of the liquid oil componentto that of the cross-linked homopolymer is in the range of about 1:1 toabout 28:1. In some embodiments, the ratio of the amount of the liquidoil component to that of the cross-linked homopolymer is in the range ofabout 1:1 to about 24:1. In some embodiments, the ratio of the amount ofthe liquid oil component to that of the cross-linked homopolymer is inthe range of about 1:1 to about 20:1. In some embodiments, this ratio isin the range of about 1:1 to about 10:1. In some embodiments, this ratiois in the range of about 2:1 to about 10:1, or in the range of about 3:1to about 10:1, or in the range of about 2:1 to about 9:1. In someembodiments, this ratio is in the range of no greater than 10:1.

In some embodiments, the oil-in-water emulsion that is formed from theliquid oil component and the cross-linked homopolymer is stable for atleast 24 hours at accelerated conditions (e.g., 40° C.). In someembodiments, the oil-in-water emulsion is stable for at least 2, 3, 4,5, 6, 7 days or longer at accelerated conditions (e.g., 40° C.). In someembodiments, the oil-in-water emulsion is stable for at least 1, 2, 3,4, 5, 6, 7, 8, 9, 10 weeks or longer at accelerated conditions (e.g.,40° C.). In some embodiments, the oil-in-water emulsion is stable for atleast 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or longer at room temperature(22-25° C.). In some embodiments, the oil-in-water emulsion is stablefor at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer atroom temperature. In some embodiments, the oil-in-water emulsion isstable for at least 1, 2, 3, 4, or 5 years or longer at roomtemperature.

In some embodiments, the composition further comprises a surfactant or across-linked copolymer of acrylic acid and acrylic acid esters as asecond emulsifier. In some embodiments, the composition comprises across-linked copolymer of acrylic acid and acrylic acid esters in anamount from about 0.01-3% by weight of the composition, or in an amountfrom about 0.01-2% by weight of the composition, or in an amount fromabout 0.01-1% by weight of the composition, or in an amount from about0.01-0.5% by weight of the composition, or in an amount from about0.01-0.3% by weight of the composition, or in an amount from about0.01-0.2% by weight of the composition. In some embodiments, thecomposition comprises a cross-linked copolymer of acrylic acid andacrylic acid esters in an amount up to about 2% by weight of thecomposition, or up to about 1% by weight of the composition, or up toabout 0.5% by weight of the composition, or up to about 0.3% by weightof the composition, or up to about 0.2% by weight of the composition.

In some embodiments, the composition further comprises a surfactant as asecond emulsifier. In some embodiments, the composition comprises anonionic, anionic, or cationic surfactant in an amount up to about 0.5%by weight of the composition, or up to about 0.4% by weight of thecomposition, or up to about 0.3% by weight of the composition, or up toabout 0.2% by weight of the composition. In some embodiments, thecomposition comprises a nonionic, anionic, or cationic surfactant in anamount of about 0.01-0.5% by weight of the composition, or in an amountof about 0.01-0.3% by weight of the composition, or in an amount ofabout 0.01-0.2% by weight of the composition. In some embodiments, thecomposition comprises a nonionic surfactant selected from the groupconsisting of sorbitan esters, polyoxyethylene derivatives of a sorbitanester, glyceryl monostearate, polyoxyethylene monooleate,polyoxyethylene monostearate and polyoxyethylene monolaurate. In someembodiments, the composition comprises an anionic surfactant selectedfrom the group consisting of an alkali soap, an amine soap, and adetergent. In some embodiments, the composition comprises a cationicsurfactant selected from the group consisting of quaternium ammoniumsalts and quaternary amine salts.

In some embodiments, the composition does not comprise a secondemulsifier. In some embodiments, the composition does not comprise across-linked copolymer of acrylic acid and acrylic acid esters. In someembodiments, the composition does not comprise a surfactant.

In some embodiments, a topical composition comprises an oil-in-wateremulsion, wherein the emulsion comprises:

-   -   a liquid oil component, wherein the liquid oil component is in        an amount of about 30% or less by weight of the composition;    -   a polymer selected from the group consisting of a cross-linked        homopolymer based on acrylic acid in an amount of about 0.01-5%        by weight of the composition, a cross-linked copolymer of        acrylic acid and acrylic acid esters in an amount of about        0.01-5% by weight of the composition, and combinations thereof;        and water.

In some embodiments, the composition comprises a cross-linkedhomopolymer based on acrylic acid in an amount of about 0.01-5% byweight of the composition. In some embodiments, the cross-linkedhomopolymer is present in an amount of about 0.01-4% by weight of thecomposition, or in an amount from about 0.01-3% by weight of thecomposition, or in an amount from about 0.01-2% by weight of thecomposition, or in an amount from about 0.01-1% by weight of thecomposition, or in an amount from about 0.05-5% by weight of thecomposition, or in an amount from about 0.05-2.5% by weight of thecomposition. In some embodiments, the cross-linked homopolymer ispresent in an amount of about 0.01%, or about 0.05%, or about 0.1%, orabout 0.2%, or about 0.3%, or about 0.4%, or about 0.5%, or about 0.6%,or about 0.7%, or about 0.8%, or about 0.9%, or about 1%, or about 1.5%,or about 2%, or about 2.5%, or about 3%, or about 3.5%, or about 4%, orabout 4.5%, or about 5% by weight of the composition.

In some embodiments, the composition comprises a cross-linked copolymerof acrylic acid and acrylic acid esters in an amount of about 0.01-5% byweight of the composition. In some embodiments, the cross-linkedcopolymer is present in an amount of about 0.01-4% by weight of thecomposition, or in an amount from about 0.01-3% by weight of thecomposition, or in an amount from about 0.01-2% by weight of thecomposition, or in an amount from about 0.01-4% by weight of thecomposition, or in an amount from about 0.05-5% by weight of thecomposition, or in an amount from about 0.05-2.5% by weight of thecomposition. In some embodiments, the cross-linked copolymer is presentin an amount of about 0.01%, or about 0.05%, or about 0.1%, or about0.2%, or about 0.3%, or about 0.4%, or about 0.5%, or about 0.6%, orabout 0.7%, or about 0.8%, or about 0.9%, or about 1%, or about 1.5%, orabout 2%, or about 2.5%, or about 3%, or about 3.5%, or about 4%, orabout 4.5%, or about 5% by weight of the composition.

In some embodiments, the composition comprises both a cross-linkedhomopolymer based on acrylic acid in an amount of about 0.01-5% byweight of the composition and a cross-linked copolymer of acrylic acidand acrylic acid esters in an amount of about 0.01-5% by weight of thecomposition. In some embodiments, the composition comprises across-linked homopolymer in an amount of about 0.01-4% by weight of thecomposition, or in an amount from about 0.01-3% by weight of thecomposition, or in an amount from about 0.01-2% by weight of thecomposition, or in an amount from about 0.01-1% by weight of thecomposition, or in an amount from about 0.05-5% by weight of thecomposition, or in an amount from about 0.05-2.5% by weight of thecomposition, and comprises a cross-linked copolymer in an amount ofabout 0.01-4% by weight of the composition, or in an amount from about0.01-3% by weight of the composition, or in an amount from about 0.01-2%by weight of the composition, or in an amount from about 0.01-1% byweight of the composition, or in an amount from about 0.05-5% by weightof the composition, or in an amount from about 0.05-2.5% by weight ofthe composition, or in an amount from about 0.05-1.5% by weight of thecomposition, or in an amount from about 0.05-1% by weight of thecomposition. In some embodiments, the composition comprises across-linked homopolymer in an amount of about 0.01%, or about 0.05%, orabout 0.1%, or about 0.2%, or about 0.3%, or about 0.4%, or about 0.5%,or about 0.6%, or about 0.7%, or about 0.8%, or about 0.9%, or about 1%,or about 1.5%, or about 2%, or about 2.5%, or about 3%, or about 3.5%,or about 4%, or about 4.5%, or about 5% by weight of the composition,and comprises a cross-linked copolymer in an amount of about 0.01%, orabout 0.05%, or about 0.1%, or about 0.2%, or about 0.3%, or about 0.4%,or about 0.5%, or about 0.6%, or about 0.7%, or about 0.8%, or about0.9%, or about 1%, or about 1.5%, or about 2%, or about 2.5%, or about3%, or about 3.5%, or about 4%, or about 4.5%, or about 5% by weight ofthe composition.

In some embodiments, the cross-linked homopolymer based on acrylic acidand the cross-linked copolymer of acrylic acid and acrylic acid estersare present in a ratio in the range of 0.1:1 to about 100:1. In someembodiments, the composition comprises both a cross-linked homopolymerbased on acrylic acid and a cross-linked copolymer of acrylic acid andacrylic acid esters, wherein the cross-linked homopolymer and thecross-linked copolymer are present in a ratio of at least 1.6:1 orgreater. In some embodiments, the cross-linked homopolymer based onacrylic acid and the cross-linked copolymer of acrylic acid and acrylicacid esters are present in a ratio in the range of 1.6:1 to about 100:1,or in the range of about 2:1 to about 100:1, or in the range of about5:1 to about 100:1, or in the range of about 10:1 to about 100:1. Insome embodiments, the cross-linked homopolymer based on acrylic acid andthe cross-linked copolymer of acrylic acid and acrylic acid esters arepresent in a ratio in the range of about 2:1 to about 50:1, or in therange of about 5:1 to about 50:1, or in the range of about 10:1 to about50:1. In some embodiments, the cross-linked homopolymer based on acrylicacid and the cross-linked copolymer of acrylic acid and acrylic acidesters are present in a ratio of at least 2:1 or greater, e.g., at least3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least8:1, at least 9:1, or at least 10:1.

In some embodiments, the liquid oil component is present in an amount ofabout 30%, or less (such as 0.5-30% or 0.5-25%), by weight of thecomposition. In some embodiments, the liquid oil component is present inan amount of about 20%, or less (such as 0.5-20%), by weight of thecomposition. In some embodiments, the liquid oil component is present inan amount of about 15% or less by weight of the composition, or about10% or less by weight of the composition, or about 8% or less by weightof the composition. In some embodiments, the liquid oil component ispresent in an amount of about 1-20% by weight of the composition, or inan amount from about 1% to about 15% by weight of the composition, or inan amount from about 1% to about 10% by weight of the composition, or inan amount from about 1% to about 5% by weight of the composition, or inan amount from about 2% to about 4% by weight of the composition. Insome embodiments, the liquid oil component is present in an amount ofabout 5-20% by weight of the composition, or in an amount of about 5-15%by weight of the composition, or in an amount of about 5-10% by weightof the composition. In some embodiments, the liquid oil component ispresent in an amount up to about 10% by weight of the composition, e.g.,up to about 8%, up to about 7.5%, up to about 7%, up to about 6%, up toabout 5%, up to about 4.5%, up to about 4%, up to about 3.5%, up toabout 3%, or up to about 2.5%.

In some embodiments, the oil component is present in an amount up toabout 5% by weight of the composition, e.g., up to about 4.5%, up toabout 4%, up to about 3.5%, up to about 3%, or up to about 2.5%. Theamount of the oil component can range from about 1.5% to about 2.5%, orfrom about 1% to about 3%, or from about 0.5% to about 3.5%, or fromabout 0.25% to about 4%, or from about 0.1% to about 5%, or from about0.05% to about 5.5% by weight of the composition. In some embodiments,the oil component is present in an amount ranging from about 2% to about4% by weight of the composition, e.g., about 2%, about 2.5%, about 3%,about 3.5%, or about 4% by weight of the composition. In someembodiments, the oil component is present in an amount ranging fromabout 1% to about 5% by weight of the composition. In some embodiments,the oil component is present in an amount ranging from about 1.5% toabout 4% by weight of the composition. In some embodiments, the oilcomponent is present in an amount ranging from about 2% to about 4% byweight of the composition. In some embodiments, the oil component ispresent in an amount ranging from about 1% to about 3% by weight of thecomposition.

In some embodiments, the liquid oil component and the polymer (e.g., thecross-linked homopolymer, the cross-linked copolymer, or the combinationof cross-linked homopolymer and cross-linked copolymer) are present in aratio in the range of about 1:1 to about 28:1. In some embodiments, theliquid oil component and the polymer (e.g., the cross-linkedhomopolymer, the cross-linked copolymer, or the combination ofcross-linked homopolymer and cross-linked copolymer) are present in aratio in the range of about 1:1 to about 20:1. In some embodiments, theliquid oil component and the polymer (e.g., the cross-linkedhomopolymer, the cross-linked copolymer, or the combination ofcross-linked homopolymer and cross-linked copolymer) are present in aratio in the range of about 1:1 to about 10:1. In some embodiments, theliquid oil component and the polymer (e.g., the cross-linkedhomopolymer, the cross-linked copolymer, or the combination ofcross-linked homopolymer and cross-linked copolymer) are present in aratio in the range of about 2:1 to about 10:1, or in the range of about3:1 to about 10:1, or in the range of about 2:1 to about 9:1. In someembodiments, the liquid oil component and the polymer (e.g., thecross-linked homopolymer, the cross-linked copolymer, or the combinationof cross-linked homopolymer and cross-linked copolymer) are present in aratio in the range of no greater than 10:1.

Polymeric Components

In some embodiments, the polymeric component is a carbomer homopolymer.In some embodiments, the carbomer homopolymer is a carbomer homopolymertype A, carbomer homopolymer type B, or carbomer homopolymer type C. Insome embodiments, a cross-linked homopolymer comprises a carbomerhomopolymer type A (e.g., a Carbopol® 981, Carbopol® 71G, or Carbopol®971P carbomer homopolymer). In some embodiments, the polymeric viscosityincreasing agent comprises carbomer homopolymer type C (e.g., aCarbopol® 980 carbomer homopolymer). In some embodiments, the carbomerhomopolymer is not Carbopol® 974P.

In some embodiments, the polymer is a cross-linked copolymer of acrylicacid and acrylic acid esters. In some embodiments, the cross-linkedcopolymer comprises a copolymer of acrylic acid and C₁₀-C₃₀ alkylacrylate. In some embodiments, the copolymer is cross-linked with allylpentacrythritol. In some embodiments, the cross-linked copolymercomprises a copolymer of acrylic acid and C₁₀-C₃₀ alkyl acrylatecross-linked with allyl pentaerythritol. In some embodiments, thecross-linked copolymer is a carbomer copolymer type B (e.g., Pemulen™TR-1) and/or a carbomer copolymer type A (e.g., Pemulen™ TR-2). In someembodiments, the cross-linked copolymer is a carbomer copolymer type B.suitable cross-linked copolymers are copolymers of acrylic acid andalkylmethacrylate, cross-linked with allyl ethers of pentaerythritol.

In some embodiments, the carbomer hompolymer type A (e.g., Carbopol®981) exhibits a viscosity ranging from about 4,000 to about 11,000 cPs;0.5% at pH 7.5. In some embodiments, the carbomer hompolymer type B(e.g., Carbopol® 974P) exhibits a viscosity ranging from about 25,000 toabout 45,000 cPs (e.g., 29,400-39,400 cPs); 0.5% at pH 7.5. In someembodiments, the carbomer hompolymer type C (e.g., Carbopol® 980)exhibits a viscosity ranging from 40,000-60,000 cPs; 0.5% at pH 7.5.Viscosity values can be determined according to known methods, includingthose described in the carbomer homopolymer monograph in USP 29-NF 24,which is incorporated herein by reference in its entirety.

In some embodiments, the carbomer homopolymer type A (e.g., Pemulen™TR-2), exhibits a viscosity ranging from about 4,500-13,500. In someembodiments, the carbomer hompolymer type B (e.g., Pemulen™ TR-1)exhibits a viscosity ranging from about 10,000 to about 26,500 cPs; 1.0%at pH 7.5. Viscosity values can be determined according to knownmethods, including those described in the carbomer copolymer monographin USP 25-NF 20, which is incorporated herein by reference in itsentirety.

Polymeric components and their properties are described in the art. See.e.g., Principles of Polymer Science and Technology in Cosmetics andPersonal Care, James V. Gruber and Des Goddard, eds., 1^(st) ed., CRCPress (1999).

Liquid Oil Component

In some embodiments, the liquid oil component comprises mineral oil,light mineral oil, a fatty alcohol, a monocarboxylic acid ester, adicarboxylic acid ester, a medium chain triglyceride, a long chaintriglyceride, or a combination thereof. In some embodiments, the liquidoil component comprises a dicarboxylic acid ester and/or amonocarboxylic acid ester. In some embodiments, the liquid oil componentcomprises medium- or long-chain triglycerides. In some embodiments, theliquid oil component comprises mineral oil.

In some embodiments, the liquid oil component comprises a dicarboxylicacid ester. In some embodiments, the dicarboxylic acid ester (DCAE) hasthe formula R₁OOC—(CH₂)n-COOR₂, wherein R₁ and R₂ are alkyl groupscontaining between 1 and 4 carbons or aryl groups and may be the same ormay be different, and wherein n is straight or branched and is between 1and 12. Examples of DCAEs containing one or more aryl groups includedibenzyl esters of dicarboxylic acids. A preferred dicarboxylic acidester is diethyl sebacate, which has the formulaCH₃CH₂OOC—(CH₂)₈—COOCH₂CH₃. Diethyl sebacate is considered to be typicalof the dicarboxylic acid esters disclosed as each of the parameters R₁,R₂, and n of diethyl sebacate are approximately in the center of therange of each of the specified parameters. Examples of other suitabledicarboxylic acid esters where R₁=R₂ include, but are not limited to,dimethyl, diethyl, dipropyl, diisopropyl, dibutyl and diisobutyl esterssuch as oxalate, malate, succinate, glutarate, adipate, pimelate,suberate, and azalate. Examples of suitable dicarboxylic acid esterswhere R₁≠R₂ include, but are not limited to, methyl ethyl, methylpropyl, methyl butyl, methyl isopropyl, ethyl propyl, ethyl butyl, ethylisopropyl, and propyl butyl esters such as oxalate, malate, succinate,glutarate, adipate, pimelate, suberate, azalate, and sebacate. In someembodiments, the liquid oil component comprises a dicarboxylic acidester selected from the group consisting of diethyl sebacate,diisopropyl adipate, and dibutyl sebecate. In some embodiments, theliquid oil component comprises diethyl sebacate. In some embodiments,the liquid oil component comprises a DCAE (e.g., diethyl sebacate) andfurther comprises mineral oil or light mineral oil.

In some embodiments, the liquid oil component comprises a monocarboxylicacid ester. In some embodiments, the monocarboxylic acid ester (MCAE) isa straight or branched alkyl MCAE, wherein the alkyl group has up to 12carbon atoms. In some embodiments, the MCAE has the formulaCH₃(CH₂)_(n)—COOR₁, wherein R₁, is an alkyl group containing between 1and 4 carbons or an aryl group, and wherein n is between 1 and 12.Examples of such monocarboxylic acid esters include, but are not limitedto, methyl, ethyl, propyl, isopropyl, butyl, or an aryl such as benzylformate, acetate, propionate, butyrate, valerate, laurate, myristate,palmitate, and stearate. Examples of preferred monocarboxylic acidesters include, but are not limited to, isopropyl palmitate andisopropyl myristate. In some embodiments, the liquid oil componentcomprises a monocarboxylic acid ester selected from the group consistingof isopropyl myristate, isopropyl palmitate, and benzyl benzoate. Insome embodiments, the liquid oil component comprises isopropylmyristate. In some embodiments, the liquid oil component comprises anMCAE (e.g., isopropyl myristate) and further comprises mineral oil orlight mineral oil.

In some embodiments, the liquid oil component is present in an amount ofabout 30%, or less (such as 0.5-30%), by weight of the composition. Insome embodiments, the liquid oil component is present in an amount ofabout 20%, or less (such as 0.5-20%), by weight of the composition. Insome embodiments, the liquid oil component is present in an amount up toabout 15% by weight of the composition. In some embodiments, the liquidoil component is present in an amount up to about 10% by weight of thecomposition. In some embodiments, the liquid oil component is present inan amount up to about 7.5% by weight of the composition. In someembodiments, the liquid oil component is present in an amount up toabout 5% by weight of the composition, e.g., up to about 4.5%, up toabout 4%, up to about 3.5%, up to about 3%, or up to about 2.5%. In someembodiments, the liquid oil component is present in an amount from about1% to about 15% by weight of the composition. In some embodiments, theliquid oil component is present in an amount from about 1% to about 10%by weight of the composition. In some embodiments, the liquid oilcomponent is present in an amount from about 1% to about 5% by weight ofthe composition. In some embodiments, the liquid oil component ispresent in an amount from about 1.5% to about 4% by weight of thecomposition. In some embodiments, the liquid oil component is present inan amount from about 2% to about 4% by weight of the composition.

In some embodiments, the oil component is present in an amount up toabout 5% by weight of the composition, e.g., up to about 4.5%, up toabout 4%, up to about 3.5%, up to about 3%, or up to about 2.5%. Theamount of the oil component can range from about 1.5% to about 2.5%, orfrom about 1% to about 3%, or from about 0.5% to about 3.5%, or fromabout 0.25% to about 4%, or from about 0.1% to about 5%, or from about0.05% to about 5.5% by weight of the composition. In some embodiments,the oil component is present in an amount ranging from about 2% to about4% by weight of the composition. e.g., about 2%, about 2.5%, about 3%,about 3.5%, or about 4% by weight of the composition. In someembodiments, the oil component is present in an amount ranging fromabout 1% to about 5% by weight of the composition. In some embodiments,the oil component is present in an amount ranging from about 1.5% toabout 4% by weight of the composition. In some embodiments, the oilcomponent is present in an amount ranging from about 2% to about 4% byweight of the composition. In some embodiments, the oil component ispresent in an amount ranging from about 1% to about 3% by weight of thecomposition.

In some embodiments, the liquid oil component and the polymer (e.g., apolymeric viscosity-increasing agent when used as a first emulsifier, ora combination of a polymeric viscosity-increasing agent and a polymericemulsifier) are present in a ratio in the range of about 1:1 to about20:1, or from about 1.5:1 to about 20:1, or from about 2:1 to about15:1, or from about 2:1 to about 10:1, or from about 2:1 to about 7.5:1,or from about 2:1 to about 5:1, or from about 2:1 to about 3:1.

Aqueous Component

in some embodiments, the pharmaceutical composition comprises water,e.g., purified water. In general, the composition comprises water in anamount such that the percentage of water and the percentages of theother components in the composition total 100% (i.e., water is addedquantum sufficit). In some embodiments, the composition comprises atleast 50% water by weight of the composition, e.g., at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, or atleast 90% water by weight of the composition.

Active Agents

In some embodiments, the compositions (e.g., topical compositions)disclosed herein comprise one or more active agents. In someembodiments, the active agent is any compound that is suitable fortopical, transdenmal or transmucosal delivery and induces a desiredlocal or systemic effect. In some embodiments, the active agent is anagent that is useful for treating a skin condition or disorder. In someembodiments, the composition comprises a cosmeceutically active agent,e.g., a nontoxic agent having a medicinal or drug-like properties which,when applied to the surface of skin, beneficially affects the biologicalfunctioning of that skin. In some embodiments, the active agent is aretinoid, a corticosteroid, an antibiotic, an anti-inflammatory agent,or an anti-fungal agent. In some embodiments, the composition comprisestwo or more active agents. In some embodiments, the compositioncomprises one, two, or three active agents. In some embodiments, whereinthe composition comprises two or more active agents, the active agentsare in the same class of agent (e.g., the active agents are bothretinoids). In some embodiments, wherein the composition comprises twoor more active agents, the active agents are in different classes ofagents (e.g., a retinoid and an antibiotic).

In some embodiments, the composition comprises a retinoid. Examples ofretinoids include, but are not limited to, retinol, retinal, tretinoin,isotretinoin, alitretinoin, etretinate, acitretin, adapalene,bexarotene, and tazarotene.

In some embodiments, the composition comprises a corticosteroid.Corticosteroids are categorized into seven classes according to theirpotency as determined based on their vasoconstrictive activity (e.g., asmeasured in a VasoConstrictor Assay). In some embodiments, thecorticosteroid is a Class 1 corticosteroid (“SuperpotentCorticosteroid”), a Class 2 corticosteroid (“Potent Corticosteroid”), ora Class 3 corticosteroid (“Upper Mid-Strength Corticosteroid”). Examplesof corticosteroids include, but are not limited to, clobetasol,halobetasol, betamethasone, fluocinonide, diflorasone, desoximetasone,mometasone, flurandrenolide, halcinonide, amcinonide, budesonide,desonide, beclomethasone, triamcinolone, fluticasone, hydrocortisone, orfluocinolone.

In some embodiments, the composition comprises an antibiotic. Examplesof antibiotics include, but are not limited to, clindamycin,erythromycin, natamycin, neomycin, mupirocin, fusidic acid, minocycline,dapsone, and tetracycline.

In some embodiments, the composition comprises an anti-inflammatoryagent. In some embodiments, the anti-inflammatory agent is an imidazolecompound that suppresses a topical inflammatory response, such as butnot limited to metronidazole. In some embodiments, the anti-inflammatoryagent is a nonsteroidal anti-inflammatory agent (NSAMD). Examples oftopical NSAIDs include, but are not limited to, ibuprofen, indomethacin,diclofenac, and naproxen.

In some embodiments, the composition comprises an anti-fungal agent.Examples of anti-fungal agents include, but are not limited to,fluconazole, itraconazole, ketoconazole, amphotericin, nystatin,pimaricin, naftifine, terbinafine, amorolfine, and 5-fluorocytosine.

In some embodiments, the active agent is present in the composition inan amount from about 0.0001% to about 10% by weight of the composition,e.g., in an amount from about 0.01% to about 1%, from about 0.01% toabout 0.5%, from about 0.05% to about 1%, from about 0.05% to about0.5%, from about 0.1% to about 1%, from about 0.1% to about 0.75%, orfrom about 0.1% to about 0.5%.

Additional Components

In some embodiments, the pharmaceutical composition (e.g., the topicalpharmaceutical composition) further comprises one or more additionalcomponents. For example, in some embodiments, the pharmaceuticalcomposition comprises one or more humectants, moisturizing agents,antioxidants, preservatives, wetting agents, and/or neutralizing agents.

In some embodiments, the pharmaceutical composition comprises one ormore moisturizing agents. Examples of suitable moisturizing agentsinclude, but are not limited to, collagen, elastin, keratin, sodiumhyaluronate, cholesterol, squalene, petrolatum, fatty acids, and fattyalcohols. In some embodiments, the moisturizing agent is a non-occlusive(e.g., non-oil) moisturizer. In some embodiments, the pharmaceuticalcomposition comprises soluble collagen and sodium hyaluronate asmoisturizing agents. In some embodiments, the one or more moisturizingagents are present in an amount from about 5% to about 20% by weight ofthe composition, e.g., from about 5% to about 15%, or from about 5% toabout 10% by weight of the composition.

In some embodiments, the pharmaceutical composition comprises one ormore humectants. Examples of suitable humectants include, but are notlimited to, glycerin, sorbitol, xylitol, urea, ethylene glycol, hexyleneglycol, polyethylene glycol, and propylene glycol. In some embodiments,the pharmaceutical composition comprises glycerin as a humectant. Insome embodiments, the one or more humectants are present in an amountfrom about 5% to about 20% by weight of the composition, e.g., fromabout 5% to about 15%, from about 7% to about 15%, or from about 7% toabout 10% by weight of the composition.

In some embodiments, the pharmaceutical composition comprises one ormore preservatives. Examples of suitable preservatives include, but arenot limited to, methyl paraben, ethyl paraben, propyl paraben, butylparaben, benzyl alcohol, benzoic acid, sorbic acid, and quaternaryammonium compounds. In some embodiments, the pharmaceutical compositioncomprises methyl paraben, propyl paraben, benzyl alcohol, or acombination thereof as the preservative(s). In some embodiments, the oneor more preservatives are present in an amount from about 0.25% to about5% by weight of the composition, e.g., from about 0.5% to about 3%, fromabout 0.5% to about 1.5%, or from about 0.25% to about 1% by weight ofthe composition.

In some embodiments, the pharmaceutical composition comprises one ormore antioxidants. Examples of suitable antioxidants include, but arenot limited to, alpha-tocopherol, ascorbic acid, butylhydoxyanisole(BHA), butylated hydoxytoluene (BHT), monothioglycerol, potassiummetabisulfite, sodium ascorbate, sodium bisulfite, sodium metabisulfite,and sodium sulfite. In some embodiments, the pharmaceutical compositioncomprises BHT as an antioxidant. In some embodiments, the one or moreantioxidants are present in an amount from about 0.1% to about 2% byweight of the composition, e.g., from about 0.15% to about 1%, fromabout 0.2% to about 1%, or from about 0.2% to about 0.6% by weight ofthe composition.

In some embodiments, the pharmaceutical composition comprises asurfactant, such as a nonionic surfactant, an anionic surfactant, or acationic surfactant. In some embodiments, the surfactant functions as asecond emulsifier. In some embodiments, the surfactant functions as awetting agent. In some embodiments, the composition comprises anonionic, anionic, or cationic surfactant in an amount up to about 0.5%by weight of the composition, or up to about 0.4% by weight of thecomposition, or up to about 0.3% by weight of the composition, or up toabout 0.2% by weight of the composition. In some embodiments, thecomposition comprises a nonionic, anionic, or cationic surfactant in anamount from about 0.05% to about 0.5% by weight of the composition, orfrom about 0.1% to about 0.5% by weight of the composition, or fromabout 0.05% to about 0.4% by weight of the composition, or from about0.1% to about 0.4% by weight of the composition, or from about 0.1% toabout 0.3% by weight of the composition. In some embodiments, thecomposition comprises a nonionic surfactant selected from the groupconsisting of sorbitan esters (e.g., sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, and sorbitantrioleate), polyoxyethylene derivatives of a sorbitan ester (e.g.,polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80),glyceryl monostearate, polyoxyethylene monooleate, polyoxyethylenemonostearate and polyoxyethylene monolaurate. In some embodiments, thecomposition comprises an anionic surfactant selected from the groupconsisting of an alkali soap, an amine soap, and a detergent. In someembodiments, the composition comprises a cationic surfactant selectedfrom the group consisting of quaternium ammonium salts and quaternaryamine salts.

In some embodiments, the pharmaceutical composition does not comprise anon-ionic surfactant. In some embodiments, the pharmaceuticalcomposition does not comprise an anionic surfactant. In someembodiments, the pharmaceutical composition does not comprise a cationicsurfactant

In some embodiments, the pharmaceutical composition comprises a pHneutralizing agent. In some embodiments, the pH neutralizing agentmaintains the pH of the pharmaceutical composition at a pH from about5-6. Suitable pH neutralizing agents include, but are not limited to,trolamine (triethanolamine), sodium hydroxide, and potassium hydroxide.In some embodiments, the pharmaceutical composition comprises trolamineas a pH neutralizing agent.

Emulsion Stability

In some embodiments, the pharmaceutical compositions disclosed hereinform a stable emulsion. In some embodiments, the pharmaceuticalcompositions disclosed herein form an emulsion (e.g., an oil-in-wateremulsion) that remains stable for a prolonged period of time and/orunder accelerated conditions. Various methods for measuring emulsionstability are known in the art. In some embodiments, emulsion stabilityis measured by centrifugation. In some embodiments, emulsion stabilityis measured by centrifugation under conditions of a centrifugal force of5000 g for at least 30 minutes. Any of a number of additional emulsionproperties can be evaluated during stability testing, such as pH,viscosity, flow behavior, tack/texture, color, odor, specific gravity,phase separation, conductivity, droplet size distribution, preservation,vibration, and or activity of the active agent (e.g., using a chemicalor biological assay). In some embodiments, emulsion stability ismeasured as disclosed in the Examples section below. In someembodiments, phase separation is measured.

In some embodiments, the composition forms an emulsion that is stableunder ambient temperature for a prolonged period of time. For example,in some embodiments, the emulsion is stable at 25° C. for at least 1month, at least 2 months, at least 3 months, at least 4 months, at least5 months, at least 6 months, at least 7 months, at least 8 months, atleast 9 months, at least 10 months, at least 11 months, or at least 12months or longer. In some embodiments, the emulsion is stable at 25° C.for at least 1 year. In some embodiments, the emulsion is stable at 25°C. for at least 2 years.

In some embodiments, the composition forms an emulsion that is stableunder accelerated conditions, such as elevated temperature (e.g., at 37°C., at 40° C., or at 45° C.). In some embodiments, the emulsion isstable for at least 24 hours at 40° C., or is stable for at least 2 daysat 40° C., or is stable for at least 3 days at 40° C., or is stable forat least 4 days at 40° C., or is stable for at least 5 days at 40° C.,or is stable for at least 6 days at 40° C., or is stable for at least 7days at 40° C. In some embodiments, the emulsion is stable for 1, 2, 3,4 weeks or longer under accelerated conditions, e.g., the emulsion isstable for at least 1 week at 40° C., or is stable for at least 2 weeksat 40° C., or is stable for at least 3 weeks at 40° C., or is stable forat least 4 weeks at 40° C., or is stable for at least 1 month at 40° C.,or is stable for at least 2 months at 40° C., or is stable for at least3 months at 40° C., or longer.

IV. Methods of Treatment

In another aspect, therapeutic methods comprising the use of apharmaceutical composition as disclosed herein are provided. In someembodiments, a pharmaceutical composition as disclosed herein is usedfor the treatment of a skin condition or disorder. In some embodiments,the skin condition or disorder is acne (e.g., acne vulgaris); psoriasis(e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustularpsoriasis, erythrodennic psoriasis, nail psoriasis, or psoriaticarthritis); dermatitis such as atopic, contact, or hand dermatitis,eczema, seborrheic dermatitis, rash, or poison ivy dermatitis; rosacea;or skin lesions. In some embodiments, a pharmaceutical composition asdisclosed herein is used cosmetically, e.g., for reducing the appearanceof fine lines, wrinkles, fine wrinkling, blotches, hyperpigmentation,skin roughness, or for the improvement of skin tone.

In some embodiments, a pharmaceutical composition as disclosed herein(e.g., a topical pharmaceutical composition comprising an active agentas disclosed in Section III above) is administered to a subject in needthereof for at least 1, 2, 3, 4, 5, 6, or 7 days or longer, e.g., for atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks or longer. In someembodiments, a pharmaceutical composition as disclosed herein isadministered to a subject in need thereof for a period of 1-30 days,e.g., 7-30 days, 7-28 days, 7-21 days, 7-14 days, 10-30 days, 14-30days, or 14-28 days. In some embodiments, a pharmaceutical compositionas disclosed herein is administered to a subject in need thereof for aperiod of 1-30 weeks, e.g., 1-20, 1-10, 1-8, 2-20, 2-15, 2-12, 2-10,2-8, 4-30, 4-20, 4-12, 4-8, 6-30, 6-20, 6-12, 8-30, 8-24, 8-12, 10-30,10-20, or 15-30 weeks.

In some embodiments, a pharmaceutical composition as disclosed herein isadministered to a subject in need thereof for a period of treatmentlonger than 2 weeks, longer than 3 weeks, longer than 4 weeks, longerthan 1 month, longer than 2 months, longer than 3 months, longer than 4months, longer than 5 months, or longer than 6 months. In someembodiments, a pharmaceutical composition as disclosed herein isadministered to a subject in need thereof for a period of treatment upto 2 weeks, up to 3 weeks, up to 4 weeks, up to 1 month, up to 2 months,up to 3 months, up to 4 months, up to 5 months, or up to 6 months. Insome embodiments, a pharmaceutical composition as disclosed herein untilimprovement or clearance of the disorder or condition (e.g., a skindisorder or condition, such as acne, psoriasis, dermatitis, rash, etc.)is achieved. In some embodiments, the pharmaceutical composition isapplied to the affected area or areas one, two, or three times a day. Insome embodiments, the pharmaceutical composition is applied to theaffected area or areas once daily. In some embodiments, thepharmaceutical composition is applied to the affected area twice daily.In some embodiments, the pharmaceutical composition is applied to theaffected area or areas up to two, three, or four times a day.

In some embodiments, a pharmaceutical composition as disclosed herein isadministered to a subject in need thereof in two or more treatmentperiods, in which the treatment periods are separated by a period oftime in which the pharmaceutical composition is not administered. Forexample, in some embodiments, a first treatment period is administeredfor a period of 1, 2, 3, 4, 5, 6, or 7 days or longer, e.g., least 1, 2,3, 4, 5, 6, 7, 8, 9, or 10 weeks or longer, then treatment is stoppedfor at least 1, 2, 3, 4, 5, 6, or 7 days or longer (e.g., for at least1, 2, 3, 4, 5 weeks or longer) before the second treatment period (e.g.,a period of 1, 2, 3, 4, 5, 6, or 7 days or longer, e.g., least 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 weeks or longer) is administered.

In some embodiments, a pharmaceutical composition as disclosed herein isadministered to an adult subject. In some embodiments, a pharmaceuticalcomposition as disclosed herein is administered to a juvenile subject.

V. Kits

In another aspect, kits comprising a pharmaceutical composition (e.g., atopical pharmaceutical composition) as disclosed herein are provided. Insome embodiments, the kit comprises a composition comprising:

-   -   a liquid oil component;    -   a cross-linked homopolymer based on acrylic acid as a first        emulsifier; and    -   water;    -   wherein the composition forms a stable oil-in-water emulsion.

In some embodiments, the kit comprises a composition comprises:

-   -   a liquid oil component, wherein the liquid oil component is in        an amount of about 30% or less by weight of the composition;    -   a polymer selected from the group consisting of a cross-linked        homopolymer based on acrylic acid in an amount of about 0.01-5%        by weight of the composition, a cross-linked copolymer of        acrylic acid and acrylic acid esters in an amount of about        0.01-5% by weight of the composition, and combinations thereof;        and    -   water.

In some embodiments, the composition further comprises an active agent.In some embodiments, the active agent is an active agent disclosed inSection III above. In some embodiments, the active agent is an agentthat is useful for treating a skin condition or disorder. In someembodiments, the active agent is a retinoid, a corticosteroid, anantibiotic, an anti-inflammatory agent, or an anti-fungal agent.

In some embodiments, the kit comprises a pharmaceutical composition foruse in the treatment of a skin condition or disorder. In someembodiments, the kit is for use in the treatment of a skin condition ordisorder that is acne (e.g., acne vulgaris); psoriasis (e.g., plaquepsoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis,erythrodermic psoriasis, nail psoriasis, or psoriatic arthritis);dermatitis such as atopic, contact, or hand dermatitis, eczema,seborrheic dermatitis, rash, or poison ivy dermatitis; rosacea; or skinlesions. In some embodiments, the kit is for use in the treatment ofacne, e.g., acne vulgaris.

In some embodiments, the kit is for cosmetic use, e.g., for reducing theappearance of fine lines, wrinkles, fine wrinkling, blotches,hyperpigmentation, skin roughness, or for the improvement of skin tone.

In some embodiments, the kit further comprises a product insert and/orinstructions for administering the pharmaceutical composition, e.g.,according to the methods disclosed herein. While instructional materialstypically comprise written or printed materials, they are not limited tosuch. Any medium capable of storing such instructions and communicatingthem to an end user is contemplated by this disclosure. Such mediainclude, but are not limited to, electronic storage media (e.g.,magnetic discs, tapes, cartridges, chips, USB drives, and SD cards),optical media (e.g., CD-ROM and DVDs) and the like. Such media mayinclude addresses to internet sites that provide such instructionalmaterials.

In some embodiments, the kit further comprises one or more other agentsfor use in the treatment of the skin disorder or condition. In someembodiments, the pharmaceutical composition as disclosed herein and theone or more other agents can be administered concurrently orsequentially.

VI. Examples

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Example 1: Formulation of Emulsion Compositions

Oil-in-water emulsion compositions are prepared as presented in Table 1below.

TABLE 1 % w/w Ingredients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 DiethylSebacate 1.5 1.5 1.5 1.5 0.0 0.0 0.0 — — — — — — — Light Mineral Oil, NF1.5 1.5 1.5 1.5 3.0 10.0  1.0 10.0  10.0  — — — — — Medium ChainTriglycerides — — — — — — — — — 3.0  10.0  3.0 10.0  3.0 CarbomerHomopolymer 0.8 0.9  0.95 1.0 1.0 1.0 1.0 0.95 0.9 0.95 0.95 1.0 0.95 —Type A (Carbopol 981), NF Carbomer Copolymer Type 0.2 0.1  0.05 0.0 0.00.0 0.0 0.05 0.1 0.05 0.05 — 0.05 — B (Pemulen TR-1), NF CarbomerHomopolymer — — — — — — — — — — — — — 1.0 Type C (Carbopol 980), NFBenzyl Alcohol, NF 0.9 Sodium Hydroxide, USP q.s. pH 5.5 ± 0.3 PurifiedWater, USP Qsad 100

Example 2: Formulation and Testing of Emulsion Compositions

Compositions that were generated and evaluated for efficiency ofpolyacrylic polymers in emulsifying a system in which its oil phaseconsisted of liquid oils that made up 11% of the total formula. Thecomponents of each composition (Formulation A-D) are presented in Table2.

TABLE 2 Formulation A B C D Ingredients % w/w Halobetasol Propionate0.01 0.01 0.01 0.01 Tazarotene 0.045 0.045 0.045 0.045 Diethyl sebacate,NF 2.97 2.97 2.97 2.97 Light mineral oil, NF 8.03 8.03 8.03 8.03Sorbitol solution, 70%, USP 10.7 10.7 10.7 10.7 Methylparaben, NF 0.170.17 0.17 0.17 Propylparaben, NF 0.03 0.03 0.03 0.03 Disodium edatatedehydrate, USP 0.05 0.05 0.05 0.05 Sorbitan monooleate, NF 0.10 0.100.10 — Pemulen TR-1 (Carbomer 0.40 — 0.40 — copolymer type B) Carbopol981 (Carbomer 0.60 0.60 — 0.60 homopolymer type A) Sodium hydroxide q.s.pH to ~5.0 Purified water q.s to 100

Formulations B and D were prepared using a carbomer homopolymer type Aas the sole emulsifier. For Formulations A and C, the ratio of liquidoil component to polymers (carbomer copolymer type B and carbomerhomopolymer type A) is 11:1. For Formulations B and D, the ratio ofliquid oil component to polymer (carbomer homopolymer type A) is about18:1.

The stability of Formulations A, B, C, and D were evaluated. Each ofFormulations A-D remained physically stable after being stored at 40° C.for a period of at least 3 months.

Example 3: Formulation of Emulsion Compostions

Oil-in-water emulsion compositions were prepared and evaluated foremulsion stability. Emulsion stability was determined by visuallyevaluating the integrity of the emulsion and confirming the absence ofphase separation. The components of each composition (Formulations 1-16)are presented below in Table 3. With the exception of Formulation 13,each of the formulations disclosed in Table 3 remained their integrityafter being stored at 50° C. for a period of 9 days.

TABLE 3 Ingredients % w/w (% w/w) 1 2 3 4 5 6 7 8 9 Diethyl Sebacate 1.51.5 1.5 1.5 1.5 1.5 1.0 — — Light Mineral 1.5 1.5 1.5 1.5 1.5 1.5 —14.0  — Oil, NF Medium Chain — — — — — — — — 3.0 Triglycerides Carbomer0.8 0.9  0.93 0.2 0.1  0.07 0.8 0.8 0.8 Homopolymer Type A (Carbopol981), NF Carbomer 0.2 0.1  0.07 0.8 0.9  0.93 0.2 0.2 0.2 Copolymer TypeB (Pemulen TR-1), NF Carbomer — — — — — — — — — Homopolymer Type B(Carbopol 974P), NF Carbomer — — — — — — — — — Homopolymer Type C(Carbopol 980), NF Benzyl Alcohol, 0.9 NF Sodium q.s. pH 5.5 ± 0.3Hydroxide, USP Trolamine, NF — — — — — — — — — Purified Water, Qsad 100USP Initial Evaluation Stable Stable Stable Stable Stable Stable StableStable Stable Ingredients % w/w (% w/w) 10 11 12 13 14 15 16 DiethylSebacate — — — — — — 1.5 Light Mineral — — — — — — 1.5 Oil, NF MediumChain 3.0 3.0 3.0 3.0 3.0 3.0 — Triglycerides Carbomer 0.2 1.0 — — — 0.80.8 Homopolymer Type A (Carbopol 981), NF Carbomer 0.8 — 1.0 — — 0.2 0.2Copolymer Type B (Pemulen TR-1), NF Carbomer — — — 1.0 — — — HomopolymerType B (Carbopol 974P), NF Carbomer — — — — 1.0 — — Homopolymer Type C(Carbopol 980), NF Benzyl Alcohol, 0.9 NF Sodium q.s. pH 5.5 ± 0.3 — —Hydroxide, USP Trolamine, NF — — — — — q.s, pH 5.5 ± 0.3 Purified Water,Qsad 100 USP Initial Evaluation Stable Stable Stable Unstable StableStable Stable

Example 4: Exemplary Tretinoin Lotion

This example provides exemplary pharmaceutical composition of thepresent disclosure for delivery of tretinoin and that is formulated as alotion, in comparison to the composition of a commercially availabletretinoin gel composition (ATRALIN® (tretinoin) gel, 0.05%).

TABLE 4 Composition of Tretinoin Lotion and ATRALIN ® Gel TretinoinATRALIN ® Ingredient Function lotion (%) gel (%) Tretinoin Anti-acne0.05 0.05 Glycerin Humectant 9.63 9.63 Soluble collagen Moisturizingagent 8.00 8.00 Carbopol ® 980 Viscosity increasing — 0.90 agentCarbomer homopol- Viscosity increasing 0.70 — ymer type A agent(Carbopol ® 981) Carbomer copol- Emulsifier 0.05 — ymer type B(Pemulen ® TR-1) Octoxynol -9 Wetting agent 0.12 0.12 Sodium hyaluronateMoisturizing agent 0.011 0.011 Methyl paraben Antimicrobial 0.20 0.20preservative Butylated Anti-oxidant 0.21 0.21 Hydroxytoluene Benzylalcohol Antimicrobial 0.50 0.50 preservative Propyl parabenAntimicrobial — 0.03 preservative Mineral oil Emollient 2.00 — TrolamineNeutralizing agent pH 5.0-6.0 pH 5.0-6.0 Water Carrier qs 100 qs 100

Manufacturing Process for Tretinoin Composition

A tretinoin composition as disclosed in Table 4 was manufacturedaccording to the following manufacturing process:

A polymeric phase is made. In a suitable manufacturing vessel, purifiedwater, Carbomer homopolymer type A (Carbopol 981), and Carbomercopolymer type B (Pemulen TR-1) are added and mixed until the contentsare dispersed. Next, mineral oil is added and mixed.

Next, a moisturizing agent is prepared. Ina separate suitable vessel,sodium hyaluronate and purified water are added and mixed until thesodium hyaluronate is dissolved. The contents of the vessel containingthe sodium hyaluronate is added to the polymeric phase and the contentsare mixed.

Next, a preservative phase is prepared. In a separate suitable vessel,glycerin is added and mixed while heating. Next, methylparaben andbenzyl alcohol are added to the vessel and the contents are mixed untildissolved. The preservative phase is added to the vessel containing thepolymeric phase, rinsed with glycerin, and mixed.

Next, an active phase is prepared. In a separate suitable vessel,purified water and glycerin are added, mixed, and blanketed withnitrogen. Next, under yellow lighting, butylated hydroxytoluene,octoxynol 9, and tretinoin are added to the vessel. The contents aremixed and then milled with recirculation. Under yellow lighting, thecontents of the vessel containing the active phase are transferred tothe vessel containing the polymeric phase, rinsed with purified water,and mixed. Next, under yellow lighting, soluble collagen is added to thevessel containing the polymeric phase and mixed.

Next, a neutralizing agent is prepared. In a separate suitable vessel,trolamine and purified water are added and mixed to form a solutionhaving a pH of 5.0-6.0.

Next, under yellow lighting, the contents of the vessel containing thepolymeric phase are transferred to a new vessel, rinsed with purifiedwater, agitated, and recirculated under nitrogen. The pH of thecomposition is determined and the pH is adjusted with the neutralizingagent as necessary. The contents of the vessel are then transferred to abulk storage container for filling secondary packaging.

Viscosity is determined in accordance with the current USP generalchapter for viscosity determination. The test conditions include atemperature of 23° t 2° C., spindle 27, and a speed of 12 rpm. Typicalviscosity of compositions of the present invention are in the range ofabout 9000 to about 11000 cP. Depending on the amounts of variouscomponents, viscosity values can range from about 2500 cP to about 18000cP.

Clinical Studies

A tretinoin lotion formulated as disclosed in Table 4 above was testedin comparison to a vehicle lotion and in comparison to a commerciallyavailable tretinoin gel, ATRALIN® (0.05% tretinoin). As describedherein, the tretinoin lotion demonstrated an unexpectedly improved localtolerability (i.e., low irritation) profile as compared to ATRALIN® gel.

The safety and efficacy of once daily use of tretinoin lotion for thetreatment of acne vulgaris were assessed in two prospective,multicenter, randomized, double-blind clinical trials in subjects 9years and older with moderate to severe acne vulgaris. The trialscompared 12 weeks of treatment with tretinoin lotion to the vehiclelotion. ATRALIN® gel and ATRALIN® gel vehicle were evaluated clinicallyin separate studies from the tretinoin lotion. The co-primary efficacyendpoints of absolute change in non-inflamatory lesion count, absolutechange in inflammatory lesion count, and “treatment success” wereassessed at Week 12. Treatment success was defined as at least a 2-gradeimprovement from Baseline in the Evaluators Global Severity Score (EGSS)score and an EGSS score equating to “clear” or “almost clear.” Table 5sets forth the EGSS scale that is used to assess the severity of thedisease state. Table 6 lists the efficacy results for trials 1 and 2.

TABLE 5 Evaluator's Global Severity Score (EGSS) Score Grade Description0 Clear Normal, clear skin with no evidence of acne 1 Almost Clear Rarenoninflammatory lesions present, with rare noninflamed papules (papulesmust be resolving and may be hyperpigmented, though not pink-red) 2 MildSome noninflammatory lesions are present, with few inflammatory lesions(papules/pustules only; no nodulocystic lesions) 3 ModerateNoninflammatory lesions predominate, with multiple inflammatory lesionsevident: several to many comedones and papules/pustules, and there mayor may not be 1 nodulocystic lesion 4 Severe Inflammatory lesions aremore apparent, many comedones and papules/pustules, there may or may notbe up to 2 nodulocystic lesions

TABLE 6 Results of Phase 3 Trials in Subjects with Acne Vulgaris at Week12 Tretinoin Tretinoin Lotion ATRALIN ® ATRALIN ® Lotion Vehicle Gel GelVehicle Trial 1 Evaluators Global Severity Score (EGSS) Clear or AlmostClear and 2-Grade 16.5% 6.9% 21% 12% Reduction from BaselineNon-Inflammatory Facial Lesions Mean Absolute Reduction 17.8 10.6 21.810.3 Mean Percent Reduction 47.5% 27.3% 43% 21% Inflammatory FacialLesions Mean Absolute Reduction 13.1 10.2  9.7  5.8 Mean PercentReduction 50.9% 40.4% 41% 26% Trial 2 EGSS Clear or Almost Clear and2-Grade 19.8% 12.5% 23% 14% Reduction from Baseline Non-InflammatoryFacial Lesions Mean Absolute Reduction 21.9 13.9 18.7 10.8 Mean PercentReduction 45.6% 31.9% 37% 20% Inflammatory Facial Lesions Mean AbsoluteReduction 13.9 10.7  7.0  4.0 Mean Percent Reduction 53.4% 41.5% 30% 17%

Improvement in Local Tolerability

Increases in signs and symptoms of local tolerability with use of aretinoid in the instant invention is an unexpected outcome. As detailedbelow, it has been surprisingly found that formulating tretinoin as alotion according to the methods disclosed herein resulted in a markedimprovement in the tolerability profile of the tretinoin, as compared tothe tolerability profile of tretinoin formulated as a gel.

Table 7 below summarizes the treatment emergent adverse events (“TEAEs”)reported in each of the programs using data from pivotal phase 3clinical studies as described above. The preferred terms are coded tothe Medical Dictionary for Regulatory Activities (MedDRA) current at thetime of each study.

TABLE 7 Comparison of Treatment Emergent Adverse Events from TretinoinLotion and ATRALIN ® Gel Clinical Studies TEASs by MedDRA OverallSummary for AE's SOC and PT (Safety Population) (Safety Subjects)Tretinoin Tretinoin Atralin Gel System Organ Class (SOC) and LotionVehicle Lotion Atralin Gel Vehicle Preferred Term (PT) (N = 767) (N =783) MedDRA (SOC) (N = 674) (N = 487) General disorders and 78 (10.2%)29 (3.7%) Skin and subcutaneous 208 (31%) 25 (5%) administration siteconditions tissue disorders Application site dryness 29 (3.8%) 1 (0.1%)Dry Skin 109 (16%) 8 (2%) Application site pain 25 (3.3%) 3 (0.4%) Painof Skin 7 (1%) 0 Application site erythema 12 (1.6%) 1 (0.1%) Erythema47 (7%) 1 (<1%) Application site pruritus 7 (0.9%) 4 (0.5%) Pruritus +Pruritus generalized 12 (2%) 3 (1%) Application site irritation 7 (0.9%)1 (0.1%) Skin irritation 3 (<1%) 0 Application site exfoliation 6 (0.8%)3 (0.4%) Skin exfoliation + skin desquamation 28 (4%) 2 (<1%)Application site dermatitis 3 (0.4%) 1 (0.1%) Dermatitis + D.exfolative + 39 (6%) 4 (1%) D. seborrheic Application site rash 3 (0.4%)0 Application site swelling 2 (0.3%) 0 Face edema + skin swelling 2(<1%) 0 Application site ulcer 2 (0.3%) 0 Ulcer 0 0 Application site bum1 (0.1%) 0 Skin burning sensation 53 (8%) 8 (2%) Application sitediscoloration 1 (0.1%) 0 Skin hypopigmentation 1 (<1%) 0 Applicationsite acne 0 2 (0.3%) Application site urticarial 0 1 (0.1%) Urticaria 1(<1%) 0 Skin and subcutaneous tissue 5 (0.7%) 6 (0.8%) disordersDermatitis contact 2 (0.3%) 1 (0.1%) Dermatitis contact 6 (1%) 1 (1%)Eczema 1 (0.1%) 1 (0.1%) Eczema + Ecz nummular + Ecz weeping 0 1 (<1%)Pityriasis rosea 1 (0.1%) 0 Pityriasis rosacea 1 (<1%) 0 Acne 0 1 (0.1%)Acne 3 (<1%) 1 (<1%) Rash 0 1 (0.1%) Rash + Rash generalized + Rashmacular + 21 (3%) 1 (<1%) Rash pruritic + Rash scaly

As shown in Table 7, tretinoin lotion demonstrated superior tolerabilityover ATRALIN® gel for several key signs and symptoms of local irritationlisted below. Note that the comparisons are presented as reportedpercentages of adverse events (“AEs”) for tretinoin lotion vs. ATRALIN®gel.

-   -   Dry skin (3.8% vs. 16%)    -   Burning (0.1% vs. 8%)    -   Erythema (1.6% vs. 7%)    -   Exfoliation (0.8% vs. 4%)

Thus, formulation of an active agent, tretinoin, in a compositioncomprising an oil-in-water emulsion comprising a liquid oil component, across-linked homopolymer based on acrylic acid (e.g., Carbopol® 981), across-linked copolymer of acrylic acid and acrylic acid esters (e.g.,Pemulen® TR-1), and water yielded a topical composition exhibitingsuperior properties as compared to a gel formulation of the activeagent.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

All publications, patents, patent applications, or other documents citedherein are hereby incorporated by reference in their entirety for allpurposes to the same extent as if each individual publication, patent,patent application, or other document was individually indicated to beincorporated by reference for all purposes.

What is claimed is:
 1. A topical composition comprising: a liquid oilcomponent; a cross-linked homopolymer based on acrylic acid as a firstemulsifier, and water; wherein the composition forms a stableoil-in-water emulsion.
 2. The topical composition of claim 1, whereinthe liquid oil component is present in an amount of about 30% or less byweight of the composition.
 3. The topical composition of claim 2,wherein the liquid oil component is present in an amount of about 20% orless by weight of the composition.
 4. The topical composition of any ofclaims 1 to 3, wherein the first emulsifer is present in an amount ofabout 0.01-5% by weight of the composition.
 5. The topical compositionof claim 4, wherein the first emulsifier is present in an amount ofabout 0.01-3% by weight of the composition.
 6. The topical compositionof any of claims 1 to 5, wherein the ratio of the amount of the liquidoil component to that of the first emulsifer is in the range of about1:1 to about 28:1.
 7. The topical composition of claim 6, wherein theratio of the amount of the liquid oil component to that of the firstemulsifer is in the range of about 1:1 to about 20:1.
 8. The topicalcomposition of claim 6 or 7, wherein the ratio of the amount of theliquid oil component to that of the first emulsifier is in the range ofabout 3:1 to about 10:1.
 9. The topical composition of any of claims 1to 8, wherein first emulsifer is a carbomer homopolymer type A and/or acarbomer homopolymer type C.
 10. The topical composition of any ofclaims 1 to 9, wherein the liquid oil component comprises mineral oil,light mineral oil, a fatty alcohol, a monocarboxylic acid ester, adicarboxylic acid ester, a medium chain triglyceride, a long chaintriglyceride, or a combination thereof.
 11. The topical composition ofany of claims 1 to 10, wherein the composition further comprises asurfactant or a cross-linked copolymer of acrylic acid and acrylic acidesters as a second emulsifier.
 12. The topical composition of claim 11,wherein the second emulsifier is a cross-linked copolymer of acrylicacid and acrylic acid esters, present in an amount of about 0.01-3% byweight of the composition.
 13. The topical composition of claim 11 or12, wherein the second emulsifer is a carbomer copolymer type B and/or acarbomer copolymer type A.
 14. The topical composition of claim 11,wherein the composition further comprises a nonionic, anionic, orcationic surfactant in an amount up to about 0.5% by weight of thecomposition.
 15. The topical composition of claim 14, wherein thenonionic surfactant is selected from the group consisting of sorbitanesters, polyoxyethytene derivatives of a sorbitan ester, glycerylmonostearate, polyoxyethylene monooleate, polyoxyethylene monostearateand polyoxyethylene monolaurate.
 16. The topical composition of claim14, wherein the anionic surfactant is selected from the group consistingof an alkali soap, an amine soap, and a detergent.
 17. The topicalcomposition of claim 14, wherein the cationic surfactant is selectedfrom the group consisting of quaternium ammonium salts and quaternaryamine salts.
 18. The topical composition of any of claims 1 to 10,wherein the composition does not comprise a second emulsifier.
 19. Thetopical composition of any of claims 1 to 18, wherein the oil-in-wateremulsion is stable for at least 24 hours at 40° C.
 20. The topicalcomposition of any of claims 1 to 19, further comprising an activeagent.
 21. The topical composition of claim 20, comprising two or moreactive agents.
 22. A topical composition, wherein the compositioncomprises an oil-in-water emulsion, wherein the emulsion comprises: aliquid oil component, wherein the liquid oil component is in an amountof about 30% or less by weight of the composition; a polymer selectedfrom the group consisting of a cross-linked homopolymer based on acrylicacid in an amount of about 0.01-5% by weight of the composition, across-linked copolymer of acrylic acid and acrylic acid esters in anamount of about 0.01-5% by weight of the composition, and combinationsthereof; and water.
 23. The topical composition of claim 22, wherein theliquid oil component is present in an amount of about 20% or less byweight of the composition.
 24. The topical composition of claim 22 or23, wherein the composition comprises a cross-linked homopolymer basedon acrylic acid in an amount of about 0.01-3% by weight of thecomposition.
 25. The topical composition of claim 22 or 23, wherein thecomposition comprises a cross-linked copolymer of acrylic acid andacrylic acid esters in an amount of about 0.01-3% by weight of thecomposition.
 26. The topical composition of any of claims 22 to 25,wherein the ratio of the amount of the liquid oil component to that ofthe polymer is in the range of about 1:1 to about 28:1.
 27. The topicalcomposition of claim 26, wherein the ratio of the amount of the liquidoil component to that of the polymer is in the range of about 1:1 toabout 20:1.
 28. The topical composition of claim 26 or 27, wherein theratio of the amount of the liquid oil component to that of the polymeris in the range of about 3:1 to about 10:1.
 29. The topical compositionof any of claims 22 to 28, wherein the liquid oil component comprisesmineral oil, light mineral oil, a fatty alcohol, a monocarboxylic acidester, a dicarboxylic acid ester, a medium chain triglyceride, a longchain triglyceride, or a combination thereof.
 30. The topicalcomposition of any of claims 22, 23, or 26 to 29, wherein the polymer isa cross-linked homopolymer based on acrylic acid.
 31. The topicalcomposition of claim 30, wherein the cross-linked homopolymer based onacrylic acid is a carbomer homopolymer type A, a carbomer homopolymertype B, or a carbomer homopolymer type C.
 32. The topical composition ofclaim 31, wherein the carbomer homopolymer is a carbomer homopolymertype A.
 33. The topical composition of any of claims 22, 23, or 26 to29, wherein the polymer is a cross-linked copolymer of acrylic acid andacrylic acid esters.
 34. The topical composition of claim 33, whereinthe cross-linked copolymer of acrylic acid and acrylic acid esters is acarbomer copolymer type B and/or a carbomer copolymer type A.
 35. Thetopical composition of any of claims 22, 23, or 26 to 29, wherein thepolymer is a combination of a cross-linked homopolymer based on acrylicacid and a cross-linked copolymer of acrylic acid and acrylic acidesters.
 36. The topical composition of claim 35, wherein the polymer isa combination of a carbomer homopolymer type A and a carbomer copolymertype B.
 37. The topical composition of claim 35, wherein the ratio ofthe amount of the cross-linked homopolymer based on acrylic acid to thatof the cross-linked copolymer of acrylic acid and acrylic acid esters isin the range of 0.1:1 to about 100:1.
 38. The topical composition ofclaim 37, wherein the ratio of the amount of the cross-linkedhomopolymer based on acrylic acid to that of the cross-linked copolymerof acrylic acid and acrylic acid esters is in the range of 1.6:1 toabout 100:1.
 39. The topical composition of any of claims 22 to 37,further comprising an active agent.
 40. The topical composition of claim39, comprising two or more active agents.